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Concurrent Administration of Immune Checkpoint Inhibitors and Stereotactic Radiosurgery Is Well-Tolerated in Patients With Melanoma Brain Metastases: An International Multicenter Study of 203 Patients

Lehrer, Eric J; Gurewitz, Jason; Bernstein, Kenneth; Kondziolka, Douglas; Fakhoury, Kareem R; Rusthoven, Chad G; Niranjan, Ajay; Wei, Zhishuo; Lunsford, L Dade; Malouff, Timothy D; Ruiz-Garcia, Henry; Peterson, Jennifer L; Bonney, Phillip; Hwang, Lindsay; Yu, Cheng; Zada, Gabriel; Deibert, Christopher P; Prasad, Rahul N; Raval, Raju R; Palmer, Joshua D; Patel, Samir; Picozzi, Piero; Franzini, Andrea; Attuati, Luca; Mathieu, David; Trudel, Claire; Lee, Cheng-Chia; Yang, Huai-Che; Jones, Brianna M; Green, Sheryl; Ahluwalia, Manmeet S; Sheehan, Jason P; Trifiletti, Daniel M
BACKGROUND:Melanoma brain metastases are commonly treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs). However, the toxicity of these 2 treatments is largely unknown when administered concurrently. OBJECTIVE:To evaluate the risk of radiation necrosis (RN) with concurrent and nonconcurrent SRS and ICIs. METHODS:The guidelines from the Strengthening the Reporting of Observational Studies in Epidemiology checklist were used. Inverse probability of treatment weighting, univariable and multivariable logistic regression, and the Kaplan-Meier method was utilized. RESULTS:There were 203 patients with 1388 brain metastases across 11 international institutions in 4 countries with a median follow-up of 15.6 months. The rates of symptomatic RN were 9.4% and 8.2% in the concurrent and nonconcurrent groups, respectively ( P =.766). On multivariable logistic regression, V12 ≥ 10 cm 3 (odds ratio [OR]: 2.76; P =.006) and presence of BRAF mutation (OR: 2.20; P =.040) were associated with an increased risk of developing symptomatic RN; the use of concurrent over nonconcurrent therapy was not associated with an increased risk (OR: 1.06; P =.877). There were 20 grade 3 toxic events reported, and no grade 4 events reported. One patient experienced a grade 5 intracranial hemorrhage. The median overall survival was 36.1 and 19.8 months for the concurrent and nonconcurrent groups (log-rank P =.051), respectively. CONCLUSION/CONCLUSIONS:Concurrent administration of ICIs and SRS are not associated with an increased risk of RN. Tumors harboring BRAF mutation, or perhaps prior exposure to targeted agents, may increase this risk. Radiosurgical optimization to maintain V12 < 10 cm 3 is a potential strategy to reduce the risk of RN.
PMID: 36255215
ISSN: 1524-4040
CID: 5360362

Modern Hearing Preservation Outcomes After Vestibular Schwannoma Stereotactic Radiosurgery

Berger, Assaf; Alzate, Juan Diego; Bernstein, Kenneth; Mullen, Reed; McMenomey, Sean; Jethanemest, Daniel; Friedmann, David R; Smouha, Eric; Sulman, Erik P; Silverman, Joshua S; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas
BACKGROUND:For patients with vestibular schwannoma (VS), stereotactic radiosurgery (SRS) has proven effective in controlling tumor growth while hearing preservation remains a key goal. OBJECTIVE:To evaluate hearing outcomes in the modern era of cochlear dose restriction. METHODS:During the years 2013 to 2018, 353 patients underwent Gamma knife surgery for VS at our institution. We followed 175 patients with pre-SRS serviceable hearing (Gardner-Robertson Score, GR 1 and 2). Volumetric and dosimetry data were collected, including biological effective dose, integral doses of total and intracanalicular tumor components, and hearing outcomes. RESULTS:The mean age was 56 years, 74 patients (42%) had a baseline GR of 2, and the mean cochlear dose was 3.5 Gy. The time to serviceable hearing loss (GR 3-4) was 38 months (95% CI 26-46), with 77% and 62% hearing preservation in the first and second years, respectively. Patients optimal for best hearing outcomes were younger than 58 years with a baseline GR of 1, free canal space ≥0.041 cc (diameter of 4.5 mm), and mean cochlear dose <3.1 Gy. For such patients, hearing preservation rates were 92% by 12 months and 81% by 2 years, staying stable for >5 years post-SRS, significantly higher than the rest of the population. CONCLUSION/CONCLUSIONS:Hearing preservation after SRS for patients with VS with serviceable hearing is correlated to the specific baseline GR score (1 or 2), age, cochlear dose, and biological effective dose. Increased tumor-free canal space correlates with better outcomes. The most durable hearing preservation correlates with factors commonly associated with smaller tumors away from the cochlea.
PMID: 35973088
ISSN: 1524-4040
CID: 5299902

Spontaneous Volumetric Tumor Regression During Wait-and-Scan Management of 952 Sporadic Vestibular Schwannomas

Marinelli, John P; Killeen, Daniel E; Schnurman, Zane; Nassiri, Ashley M; Hunter, Jacob B; Lees, Katherine A; Lohse, Christine M; Roland, Thomas J; Golfinos, John G; Kondziolka, Douglas; Link, Michael J; Carlson, Matthew L
OBJECTIVE:Spontaneous tumor shrinkage during wait-and-scan management of sporadic vestibular schwannoma is generally considered an uncommon phenomenon. However, most data informing this understanding stem from single-slice linear tumor measurements taken in the axial imaging plane. The objective of the current work was to characterize the regression capacity of sporadic vestibular schwannomas using volumetric tumor measurements. STUDY DESIGN/METHODS:Retrospective cohort study using slice-by-slice, three-dimensional volumetric tumor measurements. SETTING/METHODS:Three tertiary referral centers. PATIENTS/METHODS:Patients with sporadic vestibular schwannoma. INTERVENTIONS/METHODS:Wait-and-scan. MAIN OUTCOME MEASURES/METHODS:Regression-free survival rates with regression defined as a decrease of at least 20% of the tumor volume. RESULTS:Among 952 patients undergoing a total of 3,505 magnetic resonance imaging studies during observation, 123 experienced volumetric tumor regression after diagnosis at a median of 1.2 years (interquartile range, 0.6-2.9 yr). Volumetric regression-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after diagnosis were 94% (92-95%; 662), 86% (83-89%; 275), and 78% (73-82%; 132), respectively. Among 405 patients who demonstrated an initial period of tumor growth but continued wait-and-scan management, 48 experienced volumetric regression at a median of 1.2 years (interquartile range, 0.8-2.6 yr) after initial growth. Volumetric regression-free survival rates at 1, 3, and 5 years after initial growth were 94% (92-97%; 260), 84% (79-89%; 99), and 75% (67-83%; 43), respectively. Ultimately, only 82 of the 952 patients studied showed exclusively volumetric tumor regression (i.e., without any periods of tumor growth) by the time of last follow-up. CONCLUSION/CONCLUSIONS:Spontaneous volumetric tumor shrinkage during wait-and-scan management occurs more frequently than suggested by previous studies using linear tumor measurements and can even occur after previous episodes of documented tumor growth. These data further highlight the dynamic nature of vestibular schwannoma growth. To this end, the application of natural history data to patient management requires a nuanced approach that parallels the complex tumor behavior of vestibular schwannoma.
PMID: 36001695
ISSN: 1537-4505
CID: 5334972

Matched Comparison of Hearing Outcomes in Patients With Vestibular Schwannoma Treated With Stereotactic Radiosurgery or Observation

Schnurman, Zane; Gurewitz, Jason; Smouha, Eric; McMenomey, Sean O; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas
BACKGROUND:Previous studies comparing hearing outcomes in patients managed with stereotactic radiosurgery (SRS) and a watch-and-wait strategy were limited by small sample sizes that prevented controlling for potential confounders, including initial hearing status, tumor size, and age. OBJECTIVE:To compare hearing outcomes for patients with vestibular schwannomas (VS) managed with observation and SRS while controlling for confounders with propensity score matching. METHODS:Propensity score matching was used to compare 198 patients with unilateral VS with initial serviceable hearing (99 treated with SRS and 99 managed with observation alone) and 116 with initial class A hearing (58 managed with SRS and 58 with observation), matched by initial hearing status, tumor volume, age, and sex. Kaplan-Meier survival methods were used to compare risk of losing class A and serviceable hearing. RESULTS:Between patients with VS managed with SRS or observation alone, there was no significant difference in loss of class A hearing (median time 27.2 months, 95% CI 16.8-43.4, and 29.2 months, 95% CI 20.4-62.5, P = .88) or serviceable hearing (median time 37.7 months, 95% CI 25.7-58.4, and 48.8 months, 95% CI 38.4-86.3, P = .18). For SRS patients, increasing mean cochlear dose was not related to loss of class A hearing (hazard ratio 1.3, P = .17) but was associated with increasing risk of serviceable hearing loss (hazard ratio of 1.5 per increase in Gy, P = .017). CONCLUSION/CONCLUSIONS:When controlling for potential confounders, there was no significant difference in loss of class A or serviceable hearing between patients managed with SRS or with observation alone.
PMID: 36001782
ISSN: 1524-4040
CID: 5334982

Imaging-defined necrosis after treatment with single-fraction stereotactic radiosurgery and immune checkpoint inhibitors and its potential association with improved outcomes in patients with brain metastases: an international multicenter study of 697 patients

Lehrer, Eric J; Ahluwalia, Manmeet S; Gurewitz, Jason; Bernstein, Kenneth; Kondziolka, Douglas; Niranjan, Ajay; Wei, Zhishuo; Lunsford, L Dade; Fakhoury, Kareem R; Rusthoven, Chad G; Mathieu, David; Trudel, Claire; Malouff, Timothy D; Ruiz-Garcia, Henry; Bonney, Phillip; Hwang, Lindsay; Yu, Cheng; Zada, Gabriel; Patel, Samir; Deibert, Christopher P; Picozzi, Piero; Franzini, Andrea; Attuati, Luca; Prasad, Rahul N; Raval, Raju R; Palmer, Joshua D; Lee, Cheng-Chia; Yang, Huai-Che; Jones, Brianna M; Green, Sheryl; Sheehan, Jason P; Trifiletti, Daniel M
OBJECTIVE:Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRICs) are a frequently observed clinical manifestation and are commonly classified as imaging-defined radiation necrosis. However, these findings are not well characterized and may predict a response to SRS and ICIs. The objective of this study was to investigate predictors of TRICs and their impact on patient survival. METHODS:This retrospective multicenter cohort study was conducted through the International Radiosurgery Research Foundation. Member institutions submitted de-identified clinical and dosimetric data for patients with non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) brain metastases that had been treated with SRS and ICIs. Data were collected from March 2020 to February 2021. Univariable and multivariable Cox and logistic regression analyses were performed. The Kaplan-Meier method was used to evaluate overall survival (OS). The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRICs were determined on the basis of MRI, PET/CT, or MR spectroscopy, and consensus by local clinical providers was required. RESULTS:The analysis included 697 patients with 4536 brain metastases across 11 international institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years (IQR 58-73 years), 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% of tumors were NSCLC, melanoma, and RCC, respectively. All patients had undergone single-fraction radiosurgery to a median margin dose of 20 Gy (IQR 18-20 Gy). TRICs were observed in 9.8% of patients. The median OS for all patients was 24.5 months. On univariable analysis, Karnofsky Performance Status (KPS; HR 0.98, p < 0.001), TRICs (HR 0.67, p = 0.03), female sex (HR 0.67, p < 0.001), and prior resection (HR 0.60, p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR 0.98, p < 0.001) and TRICs (HR 0.66, p = 0.03) were associated with improved OS. A brain volume receiving ≥ 12 Gy of radiation (V12Gy) ≥ 10 cm3 (OR 2.78, p < 0.001), prior whole-brain radiation therapy (OR 3.46, p = 0.006), and RCC histology (OR 3.10, p = 0.01) were associated with an increased probability of developing TRICs. The median OS rates in patients with and without TRICs were 29.0 and 23.1 months, respectively (p = 0.03, log-rank test). CONCLUSIONS:TRICs following ICI and SRS were associated with a median OS benefit of approximately 6 months in this retrospective multicenter study. Further prospective study and additional stratification are needed to validate these findings and further elucidate the role and etiology of this common clinical scenario.
PMID: 36115055
ISSN: 1933-0693
CID: 5336602

Preoperative flow analysis of arteriovenous malformations and obliteration response after stereotactic radiosurgery

Alzate, Juan Diego; Berger, Assaf; Bernstein, Kenneth; Mullen, Reed; Qu, Tanxia; Silverman, Joshua S; Shapiro, Maksim; Nelson, Peter K; Raz, Eytan; Jafar, Jafar J; Riina, Howard A; Kondziolka, Douglas
OBJECTIVE:Morphological and angioarchitectural features of cerebral arteriovenous malformations (AVMs) have been widely described and associated with outcomes; however, few studies have conducted a quantitative analysis of AVM flow. The authors examined brain AVM flow and transit time on angiograms using direct visual analysis and a computer-based method and correlated these factors with the obliteration response after Gamma Knife radiosurgery. METHODS:A retrospective analysis was conducted at a single institution using a prospective registry of patients managed from January 2013 to December 2019: 71 patients were analyzed using a visual method of flow determination and 38 were analyzed using a computer-based method. After comparison and validation of the two methods, obliteration response was correlated to flow analysis, demographic, angioarchitectural, and dosimetric data. RESULTS:The mean AVM volume was 3.84 cm3 (range 0.64-19.8 cm3), 32 AVMs (45%) were in critical functional locations, and the mean margin radiosurgical dose was 18.8 Gy (range 16-22 Gy). Twenty-seven AVMs (38%) were classified as high flow, 37 (52%) as moderate flow, and 7 (10%) as low flow. Complete obliteration was achieved in 44 patients (62%) at the time of the study; the mean time to obliteration was 28 months for low-flow, 34 months for moderate-flow, and 47 months for high-flow AVMs. Univariate and multivariate analyses of factors predicting obliteration included AVM nidus volume, age, and flow. Adverse radiation effects were identified in 5 patients (7%), and 67 patients (94%) remained free of any functional deterioration during follow-up. CONCLUSIONS:AVM flow analysis and categorization in terms of transit time are useful predictors of the probability of and the time to obliteration. The authors believe that a more quantitative understanding of flow can help to guide stereotactic radiosurgery treatment and set accurate outcome expectations.
PMID: 36057117
ISSN: 1933-0693
CID: 5337952

Stereotactic radiosurgery for the treatment of hypoglossal schwannoma: a multi-institutional retrospective study

Dabhi, Nisha; Pikis, Stylianos; Mantziaris, Georgios; Tripathi, Manjul; Warnick, Ronald; Peker, Selcuk; Samanci, Yavuz; Berger, Assaf; Bernstein, Kenneth; Kondziolka, Douglas; Niranjan, Ajay; Lunsford, L Dade; Sheehan, Jason P
BACKGROUND:Surgical removal has been performed as the first line treatment for symptomatic or enlarging hypoglossal schwannomas (HS). Stereotactic radiosurgery (SRS) offers a minimally invasive approach that may afford long-term tumor control for patients with HS particularly those who refuse or are unfit for surgery. This study evaluates outcomes after SRS performed for both newly diagnosed and residual tumors after incomplete resection. METHODS:This retrospective, multi-institutional study involved patients treated with adjuvant or primary SRS for HS. The study end-points included local tumor response, clinical outcomes, and procedure-related complications. All the patients had Gamma Knife SRS. RESULTS:(range, 0.7-27.23). At median imaging follow-up of 37 months (range, 6-153), tumor control was achieved in 11 patients. Tumor enlargement that was managed with surgical resection was noted at the 6-month follow-up in one patient. At median clinical follow-up of 30.5 months (range, 6-157), stability, or improvement of all pre-SRS signs and symptoms was noted in nine patients. Two patients experienced worsening of at least one pre-existing symptoms or sign. New-onset trapezius weakness was noted in one patient and tongue atrophy in two patients. CONCLUSION/CONCLUSIONS:Single-fraction SRS appears to be a safe and effective upfront and adjuvant treatment option for HS. SRS may be recommended as an alternative to surgery for patients presenting with HS or as an adjuvant treatment following subtotal resection and at HS recurrence.
PMID: 35347448
ISSN: 0942-0940
CID: 5200982

Long-term Natural History and Patterns of Sporadic Vestibular Schwannoma Growth: A Multi-institutional Volumetric Analysis of 952 Patients

Marinelli, John P; Schnurman, Zane; Killeen, Daniel E; Nassiri, Ashley M; Hunter, Jacob B; Lees, Katherine A; Lohse, Christine M; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas; Link, Michael J; Carlson, Matthew L
BACKGROUND:The current study aims to characterize the natural history of sporadic vestibular schwannoma volumetric tumor growth, including long-term growth patterns following initial detection of growth. METHODS:Volumetric tumor measurements from 3,505 serial MRI studies were analyzed from unselected consecutive patients undergoing wait-and-scan management at three tertiary referral centers between 1998 and 2018. Volumetric tumor growth was defined as a change in volume ≥20%. RESULTS:Among 952 patients undergoing observation, 622 experienced tumor growth with initial growth-free survival rates (95% CI) at 1, 3, and 5 years following diagnosis of 66% (63-69), 30% (27-34), and 20% (17-24). Among 405 patients who continued to be observed despite demonstrating initial growth, 210 experienced subsequent tumor growth with subsequent growth-free survival rates at 1, 3, and 5 years following initial growth of 77% (72-81), 37% (31-43), and 24% (18-31). Larger tumor volume at initial growth (HR 1.13, p=0.02) and increasing tumor growth rate (HR 1.31; p<0.001) were significantly associated with an increased likelihood of subsequent growth, whereas a longer duration of time between diagnosis and detection of initial growth was protective (HR 0.69; p<0.001). CONCLUSIONS:While most vestibular schwannomas exhibit an overall propensity for volumetric growth following diagnosis, prior tumor growth does not perfectly predict future growth. Tumors can subsequently grow faster, slower, or demonstrate quiescence and stability. Larger tumor size and increasing tumor growth rate portend a higher likelihood of continued growth. These findings can inform timing of intervention: whether upfront at initial diagnosis, after detection of initial growth, or only after continued growth is observed.
PMID: 34964894
ISSN: 1523-5866
CID: 5108222

Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?

Berger, Assaf; Bernstein, Kenneth; Alzate, Juan Diego; Mullen, Reed; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Pavlick, Anna C; Gurewitz, Jason; Mureb, Monica; Mehnert, Janice; Madden, Kathleen; Palermo, Amy; Weber, Jeffrey S; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.
PMID: 35665462
ISSN: 1573-7373
CID: 5248172

Diplopia outcomes following stereotactic radiosurgery for petroclival or cavernous sinus meningiomas: patient series [Case Report]

Levy, Bennett R; Berger, Assaf; Kondziolka, Douglas
BACKGROUND:Skull base meningiomas (SBM) often present with diplopia due to compression of the abducens cranial nerve (CN VI). The authors evaluated outcomes in 13 patients diagnosed with SBMs who were experiencing diplopia to determine if Gamma Knife surgery (GKS) resulted in resolution of their symptoms. OBSERVATIONS/METHODS:Fourteen patients who were diagnosed with SBMs located in the cavernous sinus, clivus, or petroclival regions and presented with diplopia were treated by GKS. Demographic and clinical data as well as the duration of diplopia prior to GKS were documented. Of the 13 patients included in the study, 1 was excluded because he was lost to follow-up. For the remaining 12, diplopia was resolved in 10 (83%) and no change was noted in 2 (17%). Time to resolution was measured in months, varying from 1 to 30 months, with a median resolution time of 4.5 ± 9.7 months. Of the patients with documented postradiosurgical resolution (n = 10), the median amount of time with diplopia prior to GKS was 1.5 months (range, 1 to 20). LESSONS/CONCLUSIONS:This study showed that diplopia, related to a basal meningioma, may improve following GKS. An earlier time course to radiosurgery after diplopia onset was associated with better outcomes.
PMCID:9210270
PMID: 35733838
ISSN: 2694-1902
CID: 5282012